The K-opioid receptor (i.e., kappa-opioid receptor) is a type of opioid receptor which binds the opioid peptide dynorphin as the primary endogenous ligand. The κ opioid receptors are widely distributed in the brain, spinal cord, and in pain neurons. Kappa opioid receptors have recently been investigated for their therapeutic potential in the treatment of addiction (Hasebe K, Kawai K, Suzuki T, Kawamura K, Tanaka T, Narita M, Nagase H, Suzuki T (October 2004) “Possible pharmacotherapy of the opioid kappa receptor agonist for drug dependence” Annals of the New York Academy of Sciences 1025: 404-13) and evidence points towards dynorphin, the endogenous kappa agonist, to be one of the body's natural addiction control mechanism (Frankel P S, Alburges M E, Bush L, Hanson G R, Kish S J (July 2008) “Striatal and ventral pallidum dynorphin concentrations are markedly increased in human chronic cocaine users” Neuropharmacology 55 (1): 41-6).
In experimental “addiction” models the kappa-opioid receptor has also been shown to influence stress-induced relapse to drug seeking behavior. For the drug dependent individual, risk of relapse is a major obstacle to becoming drug free. Recent reports demonstrated that kappa-opioid receptors are required for stress-induced reinstatement of cocaine seeking (Beardsley P M, Howard J L, Shelton K L, Carroll F I (November 2005) “Differential effects of the novel kappa opioid receptor antagonist, JDTic, on reinstatement of cocaine-seeking induced by footshock stressors vs cocaine primes and its antidepressant-like effects in rats” Psychopharmacology (Berl.) 183 (1): 118-26; Redila V A, Chavkin C (September 2008). “Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system” Psychopharmacology (Berl.) 200 (1): 59-70; Blum K, Braverman E R, Holder J M, Lubar J F, Monastra V J, Miller D, Lubar J O, Chen T J, Comings D E (November 2000) “Reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors” Journal of psychoactive drugs 32 Suppl: i-iv, 1-112).
It has also been reported that the dynorphin-Kappa opioid system is critical for stress-induced drug seeking. In animal models, stress has been demonstrated to potentiate cocaine reward behavior in a kappa opioid-dependent manner (McLaughlin J P, Marton-Popovici M, Chavkin C. (July 2003) “Kappa opioid receptor antagonism and prodynorphin gene disruption block stress-induced behavioral responses” The Journal of Neuroscience 23 (13): 5674-83; Mash, Deborah C. (June 2006) “Social defeat stress-induced behavioral responses are mediated by the endogenous kappa opioid system” Neuropsychopharmacology 31 (4): 787-94). These effects are likely caused by stress-induced drug craving that requires activation of the dynorphin/kappa opioid system. Although seemingly paradoxical, it is well known that drug taking results in a change from homeostasis to allostasis. It has been suggested that withdrawal-induced dysphoria or stress-induced dysphoria may act as a driving force by which the individual seeks alleviation via drug taking. The rewarding properties of the drug are altered, and it is clear kappa-opioid activation following stress increase its rewarding properties and cause potentiation of reward behavior, or reinstatement to drug seeking. The stress-induced activation of kappa-opioid receptors is likely due to multiple signaling mechanisms. The kappa-opioid receptors have marked effects on all types of addiction including alcohol and opiate abuse.
Cocaine addiction, as well as addiction to alcohol or other drug, is a world wide problem that has serious social, mental, and physical consequences. While various forms of prevention and/or treatment of addiction have been attempted, there remains a need for an improvement. For example, small molecules have been used as drugs to decrease the physical and/or mental conditions associated with addiction. However, many small molecules with bioactivity have negative side effects due to the ability of the small molecule to not only interact with the proper receptor(s) associated with addition (e.g., target receptors), but to also cross-interact with unintended receptors (e.g., non-target receptors).